Overview Table
Overview of the 5 Viral Hepatitides
| Feature | Hep A (HAV) | Hep B (HBV) | Hep C (HCV) | Hep D (HDV) | Hep E (HEV) |
|---|---|---|---|---|---|
| Virus type | RNA | DNA | RNA | RNA | RNA |
| Transmission | Faeco-oral (e.g. contaminated water, shellfish, MSM) | Parenteral (e.g. blood to blood, sexual, vertical transmission) | Parenteral (e.g. blood to blood, vertical transmission) | Requires Hep B infection (co-infection / superinfection) | Faeco-oral (e.g. contaminated water, pork, shellfish) |
| Clinical presentation | Acute hepatitis (self-limiting) | Chronic hepatitis | Chronic hepatitis | Acute hepatitis (co-infection) or worsening of pre-existing chronic liver disease (superinfection) | Acute hepatitis (usually self-limiting but severe in pregnancy) |
| Cancer risk | None | Hepatocellular carcinoma | Hepatocellular carcinoma (via HBV) | None | |
| Treatment | Supportive care only | Antivirals (non-curative) (e.g. Tenofovir, Entecavir) | Direct-acting antivirals (curative) (e.g. sofosbuvir, glecaprevir) | Treat underlying hep B | Supportive care (ribavirin in severe cases) |
| Vaccine Available | Yes | No | |||
Hepatitis A
Aetiology
Hepatitis A virus is a non-enveloped, single-stranded RNA virus.
Hepatitis A is primarily transmitted via the faecal-oral route
- Consumption of contaminated water
- Consumption of contaminated food (esp. raw or undercooked shellfish, fruits, and vegetables from endemic regions)
- Sexual contact involving oral-anal exposure (GBMSMGay, bisexual and other men who have sex with menis a major risk factor)
Risk factors for acquiring hepatitis A:
- Poor personal hygiene (esp. after using the toilet)
- <5 y/o are key spreaders of hepatitis A (as they often have asymptomatic or mild infections and they have poor hygiene and toileting habits)
- Therefore, people who work in childcare / nursey settings are at increased risk
- GBMSMGay, bisexual and other men who have sex with men
- Travel to endemic areas- Sub-Saharan Africa<br />- South Asia (India, Bangladesh, Pakistan, Nepal)<br />- Southeast Asia (Cambodia, Indonesia, Philippines, Vietnam)<br />- Parts of Middle East<br />- Central and South America<br />- Oceania (Pacific islands) / poor sanitation areas
- Close contact with Hepatitis A patients
- People who use drugs (both injection/non-injection drugs)
- Homelessness (due to poor sanitation and crowding)
- Not vaccinated
Clinical Features
Incubation period: 15-50 days (average 28 days)
Hepatitis A typically causes acute viral hepatitis
| Prodromal phase (~1 week) | Abrupt onset of:
|
| Icteric phase (2-4 weeks) |
|
Prognosis
Hepatitis A is typically self-limiting, with most cases resolving completely within 2 months
- Rarely, severe fulminant hepatitis A can occur (most likely in those with pre-existing liver disease and older age)
Hepatitis A does NOT cause chronic hepatitis
Investigation and Diagnosis
| Serology (primary diagnostic marker) | +ve Anti-HAV IgM is the definitive serological marker for acute hepatitis A
+ve Anti-HAV IgG alone represents past infection or vaccination
|
| LFTs | Acute hepatitis gives a hepatocellular injury pattern on LFTs:
|
| Imaging | Imaging has a limited role in the diagnosis of hepatitis A:
|
PCR to detect Hep A virus RNA is mainly used in specialist settings (for early diagnosis before antibody development / serology is equivocal / monitoring infection progression).
Stool testing for HAV RNA is not routinely performed, but it can detect the virus during early infection.
Management
Management of Patient
Hepatitis A is generally self-limiting and only requires supportive care
- Advise the patient to maintain adequate hydration and nutrition
- Avoid alcohol and hepatotoxic drugs during illness
- Exclusion from work / school / nursery until 7 days after onset of jaundice (or 7 days after symptom onset, if there is no jaundice)
Hepatitis A is a notifiable infectious disease. Cases must be reported to local public health authorities promptly to allow for timely public health interventions and outbreak control.
There is no specific antiviral treatment for hepatitis A.
Management of Close Contacts
Disclaimer: Certain sections of the original guideline regarding management of close contacts have been condensed and simplified for educational purposes.
General Advice
Provide advice on good hygiene:
- In particular, careful hand washing after using the toilet (cornerstone of preventing ongoing transmission)
- Contacts whose personal hygiene is likely to be inadequate (e.g. young children, those with severe learning disabilities) should be supervised to ensure
that they wash their hands properly after defecation - Those caring for non-toilet-trained children should wash their hands immediately after nappy changing or toileting
Provide advice for those at risk of sexual transmission (e.g. GBMSM)Gay, bisexual and other men who have sex with men
- Wash hands, buttocks, groin, and penis thoroughly after sex
- Use barrier protection (condoms, dental dams, gloves) for any sexual activities including oral-anal contact
- Change condoms between anal and oral sex to prevent faeco-oral transmission
Post-Exposure Prophylaxis (PEP)
The following patients do NOT need PEP (vaccine / immunoglobulin):
- Patients who are immune
- Previous hepatitis A infection
- Complete course of hepatitis A vaccine in the past 10 years (2 monovalent doses or equivalent)
- 1 dose of monovalent vaccine within the past 12 months
- Healthy <12 m/o (if not attending childcare and if all those involved in nappy changing are immunised)
If patients do not fall under the above exclusion criteria for PEP, they would require PEP:
| Hepatitis A vaccine (single dose) |
|
| Hepatitis A vaccine + human immunoglobulin |
|
Prevention – Hepatitis A Vaccination
Hepatitis A is an inactivated vaccine, available as a monovalent (Hep A only) vaccine or in combination with Hep B or typhoid.
- A completed course of hepatitis A vaccine (2 / 3 doses, depending on the vaccine) is effective at preventing hepatitis A infection in up to 95% of recipients
Indications for hepatitis A vaccination:
- People who are travelling to or going to reside in endemic areas- Sub-Saharan Africa
- South Asia (India, Bangladesh, Pakistan, Nepal)
- Southeast Asia (Cambodia, Indonesia, Philippines, Vietnam)
- Parts of Middle East
- Central and South America
- Oceania (Pacific islands) - Chronic liver disease
- Haemophilia
- GBMSMGay, bisexual and other men who have sex with men
- People who inject drugs
- People who are at occupational risks- Laboratory staff handling hepatitis A virus or potentially infected samples
Sewage and wastewater workers exposed to human faecal material
- Staff in childcare or early-years settings where hygiene may be suboptimal
- Health-care or residential-care workers involved in feeding or toileting vulnerable patients
- Food handlers in some circumstances (particularly where hygiene facilities are limited)
References
Hepatitis B
Aetiology
Hepatitis B is an enveloped, double-stranded DNA virus
- Although it is a DNA virus, it behaves like a retrovirus during replication (via an RNA intermediate using reverse transcriptase)
Hepatitis B is primarily transmitted via the parenteral route
- Blood-to-blood
- Recipient of blood transfusions / blood-derived products before 1972 (there was no routine donor screening for HBsAg before 1972 in the UK) or in countries that do not perform screening
- IVDUIntravenous drug use (sharing or using contaminated equipment)
- Needle stick or other sharps injuries (esp. in healthcare workers)
- Tattooing and body piercing (using non-sterile equipment)
- Sexual transmission (via semen / vaginal fluids contacting mucosa microtears)
- Vertical transmission (baby is exposed to maternal blood and genital secretions during labour)
Clinical Features
Incubation period: 40-160 days (average 12 weeks)
Course of hepatitis B infection
- Most adults who acquire hepatitis B develop an acute, self-limiting hepatitis
- However, in some cases, the infection fails to clear (persists for >6 months) and becomes chronic hepatitis B
Age plays a significant role in the clinical course of hepatitis B:
- Young patients are at lower risk of acute symptomatic hepatitis B infection, but at high risk of developing chronic hepatitis
- Adults are at higher risk of acute symptomatic hepatitis B infection, but at low risk of developing chronic hepatitis
Acute Hepatitis B
Children rarely develop acute symptomatic hepatitis B infection.
1/3 of adults are symptomatic during the acute stage of infection (non-specific symptoms):
- Flu-like illness
- Nausea / vomiting
- Arthralgia
- Abdominal pain (esp. RUQ)
- Jaundice
Acute hepatitis B is usually mild and self-limiting, there is a very rare risk (<1%) of progression into severe/fulminant hepatitis.
Chronic Hepatitis B
Definition of chronic hepatitis B: virus persisting for >6 months (objectively defined as +ve HbsAgHepatitis B surface antigen<br /> persisting >6 months)
The younger the patient when infected, the higher the risk of developing chronic hepatitis B: [Ref]
- Risk is highest in infants (>90%)
- Risk is 20-50% in children (1-5 y/o)
- Risk is lowest in adults (<5%)
Chronic hepatitis B is usually asymptomatic or presents with non-specific symptoms (e.g. fatigue)
- Chronic hepatitis B often remains undiagnosed until complications develop (see below)
- However, the person remains infectious (as the virus persists in the body)
Complications
Complications of chronic hepatitis B and C are somewhat similar, therefore are presented together: [Ref1][Ref2]
| Chronic hepatitis B | Chronic hepatitis C | |
|---|---|---|
| Hepatic complication |
|
|
| Extra-hepatic complication / association |
|
3 most common comorbidities:
Other:
|
Investigation and Diagnosis
Work-Up
HBsAgHepatitis B surface antigen<br /> is the standard initial screening test for hepatitis B (as it detects both acute and chronic infection – see interpretation section below for more information)
If HBsAg is +ve, perform the following tests / investigations:
- Liver biochemistry (LFTs, serum albumin, total bilirubin, total globulins, FBC, prothrombin time)
- Full hepatitis B serology (anti-HBc IgM, HBeAg / anti-HBe)
- HBV DNA level (viral load) – used to monitor disease activity and response
- Testing for other viral hepatitides (hepatitis A, C, D) (testing for hepatitis D is important as it requires hepatitis B infection for its life cycle)
- HIV antibodies
- Testing for hepatocellular carcinoma (hepatic ultrasound + AFPAlpha-fetoprotein testing)
- Ongoing testing: 6-monthly hepatic ultrasound + AFPAlfa-fetoprotein (in those with significant fibrosis / cirrhosis)
- Testing for cirrhosis
- Initial test: transient elastography (e.g. FibroScan)
- Liver biopsy should only be considered in selected patients if the transient elastography score is <11 kPa
LFTs
Acute hepatitis B gives a hepatocellular injury pattern on LFTs (similar to other causes of acute viral hepatitis):
- ↑ AST and ALT
- Often >1,000 IU/L
- AST:ALT ratio <1
- ALT:LDH ratio >1.5
In contrast, a reduced ALT:LDH ratio (typically <1.5) is most commonly seen in ischaemic hepatitis and severe drug-induced liver injury (especially acetaminophen toxicity)
- Normal / mildly raised ALP and GGT
- ↑ Bilirubin (during the icteric phase)
However, LFTs are typically normal in chronic hepatitis B
- An isolated mildly elevated AST/ALT level may be seen
Serology Interpretation
Diagnosis of hepatitis B is made by serological testing for specific hepatitis B antigens and antibodies
Key interpretations:
| HBsAg Hepatitis B surface antigen |
Anti-HBs Antibodies to the hepatitis B surface antigen (HbsAg) |
Anti-HBcAntibodies against hepatitis B core antigen IgM | Anti-HBcAntibodies against hepatitis B core antigen IgG | |
|---|---|---|---|---|
| Acute infection | +ve | -ve | +ve | +ve |
| Chronic infection | +ve | -ve | -ve | +ve |
| Natural resolution | -ve | +ve | -ve | +ve |
| HBV vaccination | -ve | +ve | -ve | -ve |
Interpretation of some additional parameters:
- HBeAgHepatitis B e-antigen and anti-HBeAntibodies against hepatitis B e-antigen status:
- +ve HBeAg: indicates high viral load, higher infectivity and poor prognosisHBeAg is a viral protein secreted by actively replicating HBV
- +ve Anti-HBe: indicates falling viral replication, lower infectivity, and better prognosisAnti-HBe is antibody against HBeAg (which is bad, as it implies high viral load)
Development of anti-HBe appears after seroconversion, when the body's immune system suppresses viral replication
- Active vs inactive carrier state (applicable to chronic hepatitis B)
- High HBV DNA (> 2,000 IU/mL) and/or ↑ ALT = active carrier
These patients are at increased risk for progressive liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma, and generally require consideration for antiviral therapy.
- Low HBV DNA (< 2,000 IU/mL) + normal ALT = inactive carrier
- High HBV DNA (> 2,000 IU/mL) and/or ↑ ALT = active carrier
Acute vs chronic hepatitis B:
- If HBsAg remains +ve for >6 months = chronic hepatitis B
- Using anti-HBc IgM
- IgM +ve = acute hepatitis B
- IgM -ve = chronic hepatitis B (as IgM appears early in acute infection and only persists up to 6 months)
Hepatitis B infection and active hepatitis B are distinct entities:
- Hepatitis B infection simply means that the person is infected with the virus (i.e. HBsAg +ve), but there is no hepatic inflammation (normal ALT and AST levels)
- Active Hepatitis B refers to an infection that is actively causing hepatic inflammation (HBsAg +ve and ↑ ALT and AST levels)
Further Serology Interpretation:
- HBsAg is the earliest marker of hepatitis B infection – its presence indicates active infection (whether acute or chronic)
- Anti-HBs only appears after vaccination (as the vaccine only contains surface antigen) or after seroconversion (development of antibodies against HBsAg, which signifies resolution of the infection). Anti-HBs remains -ve in active infection.
- Anti-HBc IgM and IgG indicate exposure to the actual virus (not vaccination, as the vaccine only contains surface antigen but not core antigen)
- IgM persists for up to 6 months – its presence indicates acute infection
- IgG persists lifelong – its presence indicates past or current infection
Management
Hepatitis B is a notifiable disease in the UK.
Note that antiviral therapy is NOT routinely given to all patients with hepatitis B, it is reserved for patients with evidence of viral replication and/or hepatic inflammation and/or cirrhosis (see indications section for more details)
Note that hepatitis B is NOT curable with current antiviral therapy (goal is to suppress the virus); but hepatitis C is curable in >95% patients. (This is because hepatitis C does NOT integrate into host DNA, it replicates in the cytoplasm and can be cleared fully).
Antiviral Indications
To better understand & remember treatment indications it helps to know who does NOT require antiviral therapy:
- Acute hepatitis B (it is self-limiting, and only requires symptomatic treatment)
- Naturally resolved infection (seroconversion) (HBsAg -ve, anti-HBs +ve)
- Inactive carriers (HBsAg +ve, HBV DNA <2,000 IU/mL, normal ALT, minimal fibrosis)
Exam questions are unlikely to focus on the detailed indications for antiviral therapy in Hepatitis B. They are far more likely to test your understanding of which antiviral agents to use. Even if an exam does ask about treatment indications, knowing the scenarios in which antiviral therapy is not required is usually sufficient to determine the correct answer.
Indications to offer anti-viral therapy:
- Cirrhosis + detectable HBV DNA (regardless of other parameters)
- ≥30 y/o + HBV DNA > 2,000 IU/mL (high viral load) + abnormal ALT
- <30 y/o + HBV DNA > 2,000 IU/mL (high viral load) + abnormal ALT + severe liver disease (high transient elastography score [>6 kPa] or an abnormal liver biopsy [fibrosis/necroinflammation])
- HBV DNA > 20,000 IU/mL (high viral load) + abnormal ALT (regardless of age and extent of liver disease)
Choice of Antiviral Therapy
Antiviral therapy should only be initiated by an appropriate qualified healthcare professional with relevant expertise (i.e. not routinely in primary care)
Treatment choice depends on liver disease stage:
| Compensated liver disease Preserved liver synthetic function (normal serum albumin, bilirubin and coagulation parameters) AND no portal hypertension features (e.g., ascites, encephalopathy, varices). |
|
| Decompensated liver disease Presence of features of portal hypertension and/or imparied hepatic synhetic function (e.g., including ascites, varices, hepatic encephalopathy, or jaundice. Laboratory findings typically show hypoalbuminemia, elevated bilirubin, and prolonged INR). |
Offer NRTIsNucleoside reverse transcriptase inhibitors
Avoid peginterferon alpha-2a in decompensated liver disease |
| Immunomodulator | NRTIsNucleoside reverse transcriptase inhibitors | ||
|---|---|---|---|
| Recommended drug(s) |
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| MoA |
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| Route and dosing |
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| Advantages |
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| Disadvantages |
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Key point for exams: do not confuse the different classes of antivirals (they all have a similar suffix)
- Hepatitis B antiviral (peg-interferon, tenofovir, entecavir)
- HSV herpes antiviral (aciclovir, valaciclovir)
- VZV shingles antivirals (aciclovir, valaciclovir)
- CMV antivirals (ganciclovir, valganciclovir)
- Influenza antivirals (oseltamivir, zanamivir)
- HIV antiviral (NB tenofovir is used in both HIV and hepatitis B, but not entecavir) (other common HIV antivirals are emtricitabine, bictegravir, dolutegravir, abacavir, lamivudine) (see the Human Immunodeficiency Virus (HIV) article for more information)
Telbivudine is also an NRTI, but it is explicitly NOT recommended for the treatment of Hepatitis B due to its high resistance rates and inferior efficacy compared with tenofovir and entecavir.
Management of co-infections with other hepatitides:
- Co-infection with hepatitis C: peginterferon alpha + ribavirin
- Co-infection with hepatitis D: peginterferon alfa-2a
Treatment Goal
Duration of therapy depends on the antiviral and patient characteristics: [Ref1][Ref2]
- Peginterferon alpha-2a is given for a finite duration of 48weeks
- NRTIsNucleotide reverse transcriptase inhibitors (tenofovir, entecavir) are often given lifelong (as viral relapse is common)
- Suppress HBV DNA replication
- Normalise ALT
- Achieve HBeAg seroconversion in HBeAg +ve patients (i.e. loss of HBeAg and development of anti-HBe)
- Ideally, loss of HBsAg (functional cure)
Ongoing Monitoring
| Patients who are NOT taking antivirals | Monitor disease:
|
| Patients who are taking antivirals | Monitor disease:
Monitor drug side effects:
|
Hepatitis B in Pregnancy
Maternal Management
If the patient has HBV DNA >107 IU/mL, antiviral therapy is indicated:
- Give tenofovir in 3rd trimester and continue until 4-12 weeks after birth (unless the mother meets the criteria for long-term treatment)
Other recommended antivirals used for hepatitis B (entecavir and peginterferon alfa 2a) should NOT be used in pregnancy.
Neonatal Management
Neonates have the highest risk of developing chronic hepatitis B (>90%)
- Hepatitis B virus can be transmitted from the infected mother to the baby (vertical transmission)
Management of babies born to women with hepatitis B infection:
- Immediate management (after birth):
- Monovalent hepatitis B vaccine ASAP (within 24 hours) – ALL babies
- HBIGHepatitis B immune globulin ideally simultaneously with vaccine – ALL babies, unless mother is HBeAg -ve and anti-HBe +ve (indicative of seroconversion)
- Ongoing management (selective neonatal immunisation programmes)
- Give extra monovalent hepatitis B vaccine at 4 weeks
- 6 in 1 vaccine (DTaP/IPV/Hib/HepB) to be normally given in 8, 12, 16 weeks and 18 months
- HBsAg testing between 12-18 months (to identify those who develop chronic hepatitis B despite vaccination)
Mothers who are HbeAg +ve have a significantly increased risk of vertical transmission (~70-90%), without immunoprophylaxis.
Hepatitis B Immunisation
The hepatitis B vaccine is an inactivated vaccine that exists in 3 main forms:
- Monovalent (Hep B)
- Bivalent (Hep A / Hep B)
- Part of 6 in 1 (DTapdiphtheria, tetanus, acellular pertussis/IPVinactivated poliovirus/HibHaemophilus influenzae type b/HepB)
Hepatitis B Pre-Exposure Prophylaxis
Hepatitis B immunisation should be offered to:
- Infants (part of routine childhood immunisation programme) (6 in 1 vaccine at 8, 12, 16 weeks and 18 months old)
- IVDUIntravenous drug use (including those who are likely to progress – e.g. those who smoke heroin and/or cocaine)
- People who change sexual partners frequently
- GBMSMGay, bisexual, men who have sex with men
- Close contacts (sexual and household) of a person with hepatitis B
- People receiving regular blood or blood products and their carers (e.g. haemophilia, thalassaemia)
- Recipients of solid organ transplants
- Chronic renal failure (CKD 4 or 5, renal replacement therapy, renal transplantation programmes)
- Chronic liver disease (these patients should receive Hep A and B vaccine)
- People resident in prisons and places of detention
- Occupational risk (healthcare workers, laboratory staff)
Hepatitis B Post-Exposure Prophylaxis (PEP)
Significant Exposure Definition
- Percutaneous exposure
- Needle stick / other contaminated sharp object injury
- A bite which causes bleeding or visible skin puncture
- Mucocutaneous exposure to blood
- Non-intact skin
- Mucosal membrane
- Conjunctiva (eye)
- Unprotected sexual intercourse
Percutaneous exposure to contaminated blood carries the highest risk
Management Algorithm
The exact management depends on
- Exposure type (significant or non-significant)
- Patient’s HBV status (vaccinated or not? non-responder or not?)
- Source status (HBsAg +ve / unknown / HBsAg -ve)
The exact management algorithm is complicated, simplified key information is presented below.
The following information assumes that the patient had significant exposure:
| Source status | Patient immunisation status | Action |
|---|---|---|
| Unknown source / HBsAg +ve source | Fully vaccinated | → Booster dose of Hep B vaccine (if last dose is ≥1 year ago) |
| Unvaccinated | → Accelerated courseMonovalent Hep B vaccine to be given at 0, 1, 2 months +/- further dose at 12 months of Hep B vaccine +/- HBIGHepatitis B immune globulin<br /> with 1st dose | |
| Known non-respondersDefined as anti-HBs <10 mIU/mL at 1-2 months post-immunisation to Hep B vaccine | → HBIGHepatitis B immune globulin + Hep B vaccine | |
| HBsAg -ve source | Fully vaccinated | → No extra action |
| Unvaccinated | → Consider a course of Hep B vaccine | |
| Known non-respondersDefined as anti-HBs <10 mIU/mL at 1-2 months post-immunisation to Hep B vaccine | → Consider booster dose of Hep B vaccine |
Assessing Response to Vaccination
Hep B vaccines are highly effective (~90% of adults respond adequately)
- Risk factors for poor response: >40 y/o, obesity, smoking, chronic renal sufficiency
Testing for immunity post vaccination (by measuring anti-HBs) is NOT routinely recommended
- The exception is healthcare and laboratory workers → measure anti-HBs titres 1-2 months after completion of the course
- See table for actions following testing for anti-HBs response to vaccine
| Anti-HBs titre | Action |
|---|---|
| >100 mIU/mL (responder, high-titre) | No further action |
| 10-100 mIU/mL (responder, lower titre) | Give 1 additional dose of vaccine with no further action |
| <10 mIU/mL (non-responders) | Perform the following:
If still <10 mIU/mL after repeat course (= non-responder). If the patient is exposed to the virus, they will likely require HBIG for protection (see PEP section) |
References
Hepatitis C
Aetiology
Hepatitis C is an enveloped, single-stranded RNA virus
- There are 6 genotypes, the majority of infections in England are from genotypes 1 and 3
Hepatitis C is primarily transmitted via the parenteral route
- Blood-to-blood
- Recipient of blood transfusions before 1991 and blood products before 1986 (in England) (there was no routine donor screening before these years), or in countries that do not perform screening
- IVDU (sharing or using contaminated equipment)
- Needle stick or other sharps injuries (esp. in healthcare workers)
- Tattooing and body piercing (using non-sterile equipment)
- Sexual transmission (via semen / vaginal fluids contacting mucosa microtears)
- Risk is much higher in those with HIV co-infection, MSMMen who have sex with men, anal sex, oral-anal sex, presence of STIs
- Vertical transmission (baby is exposed to maternal blood and genital secretions during labour)
- Risk is higher if the mother has HIV co-infection
The transmission of hepatitis C is similar to that of hepatitis B, with a few differences:
- Blood transfusion risk differs
- Hepatitis C: before 1991
- Hepatitis B: before 1972 (screening began much earlier)
- Sexual transmission is far less efficient in hepatitis C compared to hepatitis B
- Vertical transmission is less common in hepatitis C compared to hepatitis B
IVDUIntravenous drug use is associated with increased risk for several types of viral hepatitis, but is most strongly linked to hepatitis C. [Ref]
Clinical Features
Course of hepatitis C infection
- Most adults who acquire hepatitis C develop an acute, self-limiting hepatitis
- ~80% patients with acute infection progress to chronic hepatitis C
Acute Hepatitis C
60% patients are asymptomatic, if symptomatic (non-specific):
- Flu-like illness
- Nausea / vomiting
- Arthralgia
- Abdominal pain (esp. RUQ)
- Jaundice
Jaundice is less common in acute hepatitis C than in hepatitis A or B, and most cases do not present with marked hyperbilirubinemia.[Ref]
Chronic Hepatitis C
Chronic hepatitis C is usually asymptomatic or presents with non-specific symptoms (e.g. fatigue)
- Chronic hepatitis C often remains undiagnosed until complications develop (see below)
- However, the person remains infectious (as the virus persists in the body)
Patients co-infected with HIV-1 have a poorer prognosis than those with HCVhepatitis C virus infection alone.
Complications
Complications of chronic hepatitis C and B are somewhat similar, therefore are presented together: [Ref1][Ref2]
| Chronic hepatitis C | Chronic hepatitis B | |
|---|---|---|
| Hepatic complication |
|
|
| Extra-hepatic complication / association | 3 most common comorbidities:
Other:
|
|
Investigation and Diagnosis
Work-Up
- Initial screening test: anti-HCV antibody
- If anti-HCV antibody +ve → test for HCV RNA to demonstrate the presence of the virus
Acute vs chronic hepatitis C:
- If HCV RNA remains +ve for >6 months = chronic hepatitis C
Active hepatitis C infection is diagnosed by the presence of detectable HCV RNA.
Anti-HCV antibodies become detectable 5-12 weeks after an acute infection and stay +ve lifelong, even if the virus is cleared or treated with antivirals. Therefore, +ve anti-HCV antibodies only indicate exposure to HCV at some point (resolved or current infection), they CANNOT reliably diagnose an active infection.
Baseline investigations for confirmed hepatitis C:
- HIV testing
- Hepatitis A status (HAV-IgM) and hepatitis B status (HBsAg or anti-HBc)
- Liver biochemistry (LFTs, serum albumin, total bilirubin, total globulins, FBC, prothrombin time)
- U&E
- HbA1c (diabetes is a possible extrahepatic manifestation of hepatitis C infection)
- Ferritin level
- TFTsThyroid function tests
LFTs
Acute hepatitis C gives a hepatocellular inury pattern on LFTs:
- ↑ AST and ALT
- Often >1,000 IU/L
- AST:ALT ratio <1
- ALT:LDH ratio >1.5
In contrast, a reduced ALT:LDH ratio (typically <1.5) is most commonly seen in ischaemic hepatitis and severe drug-induced liver injury (especially acetaminophen toxicity)
- Normal / mildly raised ALP and GGT
- ↑ Bilirubin (during the icteric phase)
However, LFTs are typically normal in chronic hepatitis C
- A mildly elevated AST/ALT level may be seen
Management
Hepatitis C is a notifiable disease in the UK.
Note that hepatitis B is NOT curable with current antiviral therapy (goal is to suppress the virus); however, hepatitis C is curable in >95% patients. (This is because hepatitis C does NOT integrate into host DNA, it replicates in the cytoplasm and can be cleared fully).
All patients with chronic hepatitis C should be considered for antiviral therapy
- Antiviral therapy should always be initiated by a specialist
- Patients with spontaneous resolution (loss of HCV RNA within the first 6 months) do NOT need antiviral therapy
- Acute hepatitis C infection does NOT need antiviral therapy
1st line antiviral therapy: direct-acting antivirals (DAAs)
- Genotype testing was traditionally used to guide therapy, but with the availability of modern pangenotypic DAA combinations, genotype is often not required for regimen selection in the UK
- DAAs are always given in combination, as a once daily oral tablet for 8 or 12 weeks (>90% effective, and most effective when given before onset of cirrhosis)
- DAA monotherapy does not reliably cover all genotypes and allows rapid resistance
- Combination therapy targets multiple steps in the viral life cycle, preventing resistance and achieving a cure
- The treatment goal is sustained virological response (which equates to ‘cure’)
Exam questions are unlikely to require recall of the exact DAA names or specific drug combinations. It is usually sufficient to know that DAAs are the standard treatment for chronic Hepatitis C. The following details are provided for completeness.
Commonly used 1st line regimen (sofosbuvir and 2 other suffixes: -previr and -asvir)
- 1st line is typically sofosbuvir + velpatasvir or glecaprevir + pibrentasvir
- 2nd line (DAA failures): sofosbuvir + velpatasvir + voxilaprevir
DAAs for hepatitis C are currently NOT recommended for use in pregnancy, due to insufficient safety data.
Key point for exams: do not confuse the different classes of antivirals (they all have a similar suffix)
- Hepatitis B antiviral (peg-interferon, tenofovir, entecavir)
- HSV herpes antiviral (aciclovir, valaciclovir)
- VZV shingles antiviral (aciclovir, valaciclovir)
- CMV antiviral (ganciclovir, valganciclovir)
- Influenza antiviral (oseltamivir, zanamivir)
- HIV antiviral (NB tenofovir is used in both HIV and hepatitis B, but not entecavir) (other common HIV antivirals are emtricitabine, bictegravir, dolutegravir, abacavir, lamivudine) (see the Human Immunodeficiency Virus (HIV) article for more information)
Hepatitis C Immunisation
There is NO hepatitis C vaccine available.
There is no effective post-exposure prophylaxis after exposure.
References
Hepatitis D
Aetiology
Hepatitis D is a defective, enveloped, single-stranded RNA virus [Ref]
- Hepatitis D cannot replicate or infect on its own, it requires the HBsAgHepatitis B surface antigen from hepatitis B virus to form its viral envelope (thus ‘defective’)
- Therefore, HDV infection only occurs in those with hepatitis B infection (either as co-infection or superinfection)
Clinical Features
The clinical presentation of hepatitis D infection depends on the type of infection: [Ref]
- HDV-HBV co-infection → acute hepatitis syndrome (just like acute hepatitis B infection, but the risk of acute liver failure is higher than HBV monoinfection)
- HDV superinfection in a person with chronic HBV → rapid worsening of pre-existing chronic liver disease (including rapid progression to cirrhosis)
Diagnosis
Hepatitis D status should be routinely checked for in those with hepatitis B [Ref]
- Anti-HDV antibodies indicate exposure
- HDV RNA is used to confirm active infection
Just like hepatitis B, hepatitis D is primarily transmitted via the parenteral route
Management
NICE guidelines recommend treating HDV-HBV co-infection with peginterferon alfa-2a
Hepatitis E
Aetiology
Hepatitis E is a non-enveloped single-stranded RNA virus
Similar to hepatitis A, hepatitis E is primarily transmitted via the faecal-oral route [Ref]
- Consumption of contaminated water
- Consumption of raw / undercooked meat from infected animals (notably pigs, wild boar, deer)
- Including direct contact with these animals
- Consumption of contaminated shellfish
Clinical Features
Mostly asymptomatic infection or self-limiting acute hepatitis.
Importantly, hepatitis E in pregnant women (esp. 3rd trimester) is more likely to cause fulminant hepatic failure (high maternal mortality) [Ref]
Investigation and Diagnosis
Test for: [Ref]
- HEV IgM antibodies
- HEV RNA
Management
Supportive care is the mainstay of management of acute hepatitis E (even in pregnant women) [Ref]
- Ribavirin (an antiviral) can be used in chronic hepatitis E (rare and almost exclusively in immunocompromised patients)
- Ribavirin is contraindicated in pregnancy, and there is NO established antiviral therapy for hepatitis E in pregnancy